Postoperative Pain in Infants
Conditions
Keywords
ketorolac pharmacokinetics, ketorolac stereo-isomers, infants, postoperative analgesia, safety
Brief summary
Infants handle ketorolac differently than adults. Study of handling of this pain medication given to infants following surgery. Detailed analysis of how the drug is eliminated from age 2 months to 18 months. Compared morphine use in infants who received the drug to the group getting placebo. Safety testing for kidney and liver function, breathing measured by continuous oximetry, and any bleeding issues.
Detailed description
Population kinetic analysis of ketorolac stereo-isomer concentrations after single dose given postoperatively in infants aged 2-18 months. Safety assessments of renal and hepatic function tests by blood tests before and after drug administration, urinalysis pre- and post-drug, continuous oximetry before and for 12 hours after drug. Morphine use between active drug groups and placebo group in the first 24 hours after surgery was assessed as a surrogate analgesic measure in these non-verbal infants. A modified infant pain scale was used to assure consistent pain management.
Interventions
DRUGKetorolac Tromethamine 1 mg/kg
Ketorolac Tromethamine 1 mg/kg infusion over 10 minutes intravenous (IV) infusion. Blood sampling in for up to 12 hours after infusion for analysis of ketorolac concentrations and safety assessments.
DRUGKetorolac Tromethamine 0.5 mg/kg
Ketorolac Tromethamine 0.5 mg/kg infusion over 10 minutes intravenous (IV) infusion. Blood sampling for up to 12 hours after infusion for analysis of ketorolac concentrations and safety assessments.
DRUGPlacebo
Dextrose in water (D5W) infusion over 10 minutes intravenous (IV) infusion. Blood sampling for up to 12 hours after infusion for analysis of ketorolac concentrations and safety assessments.
Sponsors
University of Washington
Seattle Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Months to 18 Months
Healthy volunteers
No
Inclusion criteria
* Non-prematurely-born infants admitted to hospital following surgery ages 2-18 months, studied by age group 12-18 months, 6-12 months, \< 6 months
Exclusion criteria
* Bleeding history in infant or family * Coagulopathy * Gastrointestinal bleeding history * Renal or hepatic disease assessed by history and by pre-drug blood tests * Premature birth (\<36 weeks gestation)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Half-life of Ketorolac Stereo-isomers in 6-18 Month Old Infants After Surgery | 24 hours after surgery | noncompartmental pharmacokinetic analysis of ketorolac stereo-isomers after intravenous infusion in postoperative infants |
| Half-life of S- and R+ Ketorolac in 2-6 Month Old Infants | 24 hours after surgery | half-life calculated from non-compartmental analysis of ketorolac isomers in 2-6 month old infants given intravenous ketorolac following surgery |
| Clearance of S- and R+ Ketorolac in 6-18 Month Old Infants | 24 hours after surgery | stereo-specific ketorolac clearance by population-based analysis (NONMEM) |
| Volume of Distribution for Ketorolac Isomers in 6-18 Month Old Infants | 24 hours after surgery | population-based kinetic analysis of ketorolac isomers following intravenous infusion in infants after surgery |
| Ketorolac Stereo-isomer Volume of Distribution Peripheral in 6-18 Month Old Infants | 24 hours after surgery | population-based analysis of ketorolac stereo-isomers |
| Clearance of S-ketorolac and R+ Ketorolac in 2-6 Month Old Infants Following Surgery | 24 hours following surgery | stereo-isomer specific clearance determined by population-based pharmacokinetic analysis (NONMEM) |
| Central Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants | 24 hours after surgery | stereo-specific ketorolac analysis using population-based analysis (NONMEM)for ketorolac given intravenously 24 hours after surgery in 2-6 month old infants |
| Peripheral Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants | 24 hours post surgery | peripheral volume of distribution for ketorolac stereo-isomers determined by population kinetic analysis (NONMEM) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Time With Room Air Oximetry Saturations Under 90% in 2-6 Month Infants | 12 hours after ketorolac or placebo infusion | continuous oximetry monitoring of room air saturation was collected for 12 hours after intravenous infusion of ketorolac or placebo |
| Total Morphine Use in 6-18 Month Old Infants After Ketorolac or Placebo Intravenous Infusion After Surgery | 24 hours after surgery | total amount of morphine given for 12 hours after ketorolac or placebo infusion in 6-18 month old infants after surgery |
| Oximetry Saturation Under 90% After Ketorolac or Placebo Infusion in 6-18 Month Old Infants | 24 hours after surgery | continuous oximetry monitoring for 12 hours after ketorolac or placebo intravenous infusion in 6-18 month old infants after surgery |
| Morphine Use in 2-6 Month Old Infants Given Ketorolac or Placebo Following Surgery | first day after surgery | total morphine given intravenously in the 12 hours following receiving intravenous ketorolac or placebo |
Countries
United States
Participant flow
Recruitment details
Infants less than 18 months of age, having surgery requiring inpatient admission, from 2001 through 2008, with normal renal and liver function, not on chronic medication , not prematurely born, were selected.
Pre-assignment details
If screening lab studies (blood urea nitrogen \[BUN\], creatinine, liver transaminase concentrations, urinalysis) were abnormal infants were excluded. If postoperative concerns precluded blood sampling or if sampling intravenous (iv) catheters did not function, infants were excluded.Of 77 infants screened, 51 infants started study
Participants by arm
| Arm | Count |
|---|---|
| Ketorolac 1 mg/kg Intravenous intravenous infusion over 10 minutes | 22 |
| Ketorolac 0.5 mg/kg Intravenous intravenous infusion over 10 minutes | 11 |
| Dextrose 5% in Water (D5W) intravenous infusion over 10 minutes | 18 |
| Total | 51 |
Baseline characteristics
| Characteristic | Ketorolac 0.5 mg/kg Intravenous | Dextrose 5% in Water (D5W) | Ketorolac 1 mg/kg Intravenous | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 18 Participants | 22 Participants | 51 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 9.4 months STANDARD_DEVIATION 4.2 | 9 months STANDARD_DEVIATION 3.8 | 8.9 months STANDARD_DEVIATION 3.8 | 9.1 months STANDARD_DEVIATION 3.9 |
| Region of Enrollment United States | 11 participants | 18 participants | 22 participants | 51 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 12 Participants | 26 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 10 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 22 | 0 / 11 | 0 / 18 |
| serious Total, serious adverse events | 0 / 22 | 0 / 11 | 0 / 18 |
Outcome results
Primary
Central Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants
stereo-specific ketorolac analysis using population-based analysis (NONMEM)for ketorolac given intravenously 24 hours after surgery in 2-6 month old infants
Time frame: 24 hours after surgery
Population: infants enrolled but did not complete protocol if abnormal laboratory studies or intravenous catheters were not functioning prior to study drug infusion. Of 77 enrolled, 51 completed study; of the 33 given ketorolac,8 were aged 2-6 months. Doses of 0.5 or 1 mg/kg were handled similarly so reported together.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Central Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants | 1480 ml | Standard Error 920 |
| R+ Ketorolac Clearance | Central Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants | 992 ml | Standard Error 440 |
Primary
Clearance of S- and R+ Ketorolac in 6-18 Month Old Infants
stereo-specific ketorolac clearance by population-based analysis (NONMEM)
Time frame: 24 hours after surgery
Population: 52 infants aged 6-18 months enrolled; 15 excluded for abnormal laboratory results or intravenous sampling catheters that did not allow sampling. 25 infants aged 6-18 months received ketorolac, 12 received placebo. Doses of 0.5 or 1 mg/kg reported together since no difference found in handling.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Clearance of S- and R+ Ketorolac in 6-18 Month Old Infants | 45.3 ml/min | Standard Error 12.1 |
| R+ Ketorolac Clearance | Clearance of S- and R+ Ketorolac in 6-18 Month Old Infants | 7.52 ml/min | Standard Error 9.3 |
Primary
Clearance of S-ketorolac and R+ Ketorolac in 2-6 Month Old Infants Following Surgery
stereo-isomer specific clearance determined by population-based pharmacokinetic analysis (NONMEM)
Time frame: 24 hours following surgery
Population: of 25 infants aged 2-6 months enrolled, 11 were excluded. 8 received drug, 6 received placebo; this is a subset of the 77 enrolled infants (aged 2-18 months) of whom 51 completed the study. Infants receiving drug at 0.5 or 1 mg/kg were reported together, since no difference in drug handling was seen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Clearance of S-ketorolac and R+ Ketorolac in 2-6 Month Old Infants Following Surgery | 30.7 ml/min | Standard Error 22.8 |
| R+ Ketorolac Clearance | Clearance of S-ketorolac and R+ Ketorolac in 2-6 Month Old Infants Following Surgery | 6.5 ml/min | Standard Error 2.2 |
Primary
Half-life of Ketorolac Stereo-isomers in 6-18 Month Old Infants After Surgery
noncompartmental pharmacokinetic analysis of ketorolac stereo-isomers after intravenous infusion in postoperative infants
Time frame: 24 hours after surgery
Population: 52 infants of the 77 total were aged 6-18 months. 15 were excluded for abnormal laboratory values at screening or for lack of access to draw blood samples. 25 received drug, 12 placebo.Doses 0.5 or 1 mg/kg reported together since no difference in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Half-life of Ketorolac Stereo-isomers in 6-18 Month Old Infants After Surgery | 50.1 min | Standard Deviation 42 |
| R+ Ketorolac Clearance | Half-life of Ketorolac Stereo-isomers in 6-18 Month Old Infants After Surgery | 238 min | Standard Deviation 48 |
Primary
Half-life of S- and R+ Ketorolac in 2-6 Month Old Infants
half-life calculated from non-compartmental analysis of ketorolac isomers in 2-6 month old infants given intravenous ketorolac following surgery
Time frame: 24 hours after surgery
Population: total infants enrolled was 77; 26 were excluded before study procedures began. Of 51 infants completing the study, 8 infants aged 2-6 months received drug.No difference in analysis at doses of 0.5 or 1 mg/kg so reported together.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Half-life of S- and R+ Ketorolac in 2-6 Month Old Infants | 67 min | Standard Error 33 |
| R+ Ketorolac Clearance | Half-life of S- and R+ Ketorolac in 2-6 Month Old Infants | 197 min | Standard Error 82 |
Primary
Ketorolac Stereo-isomer Volume of Distribution Peripheral in 6-18 Month Old Infants
population-based analysis of ketorolac stereo-isomers
Time frame: 24 hours after surgery
Population: 52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac, 12 received placebo. Drug handling not different at doses of 0.5 or 1 mg/kg so reported together.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Ketorolac Stereo-isomer Volume of Distribution Peripheral in 6-18 Month Old Infants | 224 ml | Standard Error 86 |
| R+ Ketorolac Clearance | Ketorolac Stereo-isomer Volume of Distribution Peripheral in 6-18 Month Old Infants | 828 ml | Standard Error 13 |
Primary
Peripheral Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants
peripheral volume of distribution for ketorolac stereo-isomers determined by population kinetic analysis (NONMEM)
Time frame: 24 hours post surgery
Population: 25 infants aged 2-6 months enrolled; 11 excluded for no sampling intravenous access. 8 infants received drug, 6 received placebo. No difference in analysis of doses of 0.5 or 1 mg/kg so reported together.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Peripheral Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants | 341 ml | Standard Deviation 342 |
| R+ Ketorolac Clearance | Peripheral Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants | 658 ml | Standard Deviation 207 |
Primary
Volume of Distribution for Ketorolac Isomers in 6-18 Month Old Infants
population-based kinetic analysis of ketorolac isomers following intravenous infusion in infants after surgery
Time frame: 24 hours after surgery
Population: of 52 enrolled infants aged 6-18 months, 37 completed the study. Of these, 25 received drug, 12 placebo.Doses of 0.5 or 1 mg/kg showed no difference in handling so reported together.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Volume of Distribution for Ketorolac Isomers in 6-18 Month Old Infants | 2320 ml | Standard Error 14.6 |
| R+ Ketorolac Clearance | Volume of Distribution for Ketorolac Isomers in 6-18 Month Old Infants | 1200 ml | Standard Error 13.6 |
Secondary
Morphine Use in 2-6 Month Old Infants Given Ketorolac or Placebo Following Surgery
total morphine given intravenously in the 12 hours following receiving intravenous ketorolac or placebo
Time frame: first day after surgery
Population: 25 infants enrolled but 11 excluded. 8 received ketorolac, 6 placebo. total morphine given over 12 hours following infusion collected
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Morphine Use in 2-6 Month Old Infants Given Ketorolac or Placebo Following Surgery | 0.12 mg/kg | Standard Deviation 0.28 |
| R+ Ketorolac Clearance | Morphine Use in 2-6 Month Old Infants Given Ketorolac or Placebo Following Surgery | 0.08 mg/kg | Standard Deviation 0.12 |
Secondary
Oximetry Saturation Under 90% After Ketorolac or Placebo Infusion in 6-18 Month Old Infants
continuous oximetry monitoring for 12 hours after ketorolac or placebo intravenous infusion in 6-18 month old infants after surgery
Time frame: 24 hours after surgery
Population: 52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac, 12 received placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Oximetry Saturation Under 90% After Ketorolac or Placebo Infusion in 6-18 Month Old Infants | 0.8 per cent time of 12 hours | Standard Deviation 0.8 |
| R+ Ketorolac Clearance | Oximetry Saturation Under 90% After Ketorolac or Placebo Infusion in 6-18 Month Old Infants | 1 per cent time of 12 hours | Standard Deviation 1 |
Secondary
Percent Time With Room Air Oximetry Saturations Under 90% in 2-6 Month Infants
continuous oximetry monitoring of room air saturation was collected for 12 hours after intravenous infusion of ketorolac or placebo
Time frame: 12 hours after ketorolac or placebo infusion
Population: 25 infants aged 2-6 months enrolled; 11 excluded. 8 received ketorolac, 6 placebo
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| S- Ketorolac Clearance | Percent Time With Room Air Oximetry Saturations Under 90% in 2-6 Month Infants | NA percentage of time in 12 h after drug |
| R+ Ketorolac Clearance | Percent Time With Room Air Oximetry Saturations Under 90% in 2-6 Month Infants | NA percentage of time in 12 h after drug |
Secondary
Total Morphine Use in 6-18 Month Old Infants After Ketorolac or Placebo Intravenous Infusion After Surgery
total amount of morphine given for 12 hours after ketorolac or placebo infusion in 6-18 month old infants after surgery
Time frame: 24 hours after surgery
Population: 52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac and 12 received placebo infusion after surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| S- Ketorolac Clearance | Total Morphine Use in 6-18 Month Old Infants After Ketorolac or Placebo Intravenous Infusion After Surgery | 1.8 mg/kg | Standard Deviation 1.5 |
| R+ Ketorolac Clearance | Total Morphine Use in 6-18 Month Old Infants After Ketorolac or Placebo Intravenous Infusion After Surgery | 2.2 mg/kg | Standard Deviation 1.4 |